MACROCYCLIC COMPOUNDS AS INHIBITORS OF VIRAL REPLICATION
The embodiments provide compounds of the general formulas I-XIX, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating flaviviral infection, including hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
1 . A compound of the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
(a) Z is a group configured to hydrogen bond to an NS3 protease His57 imidazole moiety and to hydrogen bond to a NS3 protease Gly137 nitrogen atom;
(b) P 1 ′ is a group configured to form a non-polar interaction with at least one NS3 protease S1′ pocket moiety selected from the group consisting of Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42, and Phe43;
(c) L is a linker group consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
(d) P 2 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; P 2 being positioned by L to form a non-polar interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81;
(e) the dashed line represents an optional double bond;
(f) R 5 is selected from the group consisting of H, C(O)NR 6 R 7 and C(O)OR 8 ;
(g) R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and
(h) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 8 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 8 is C 1-6 alkyl optionally substituted with up to 5 fluoro groups; or R 8 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 8 is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring.
2 . The compound of claim 1 , wherein the C 13 -C 14 double bond is cis.
3 . The compound of claim 1 , wherein the C 13 -C 14 double bond is trans.
4 . The compound of claim 1 , wherein P 2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle.
5 . The compound of claim 1 , wherein P 2 is
6 . The compound of claim 1 , wherein L consists of from 1 to 5 atoms selected from the group consisting of nitrogen, hydrogen and sulfur.
7 . The compound of claim 1 , wherein L consists of from 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur.
8 . The compound of claim 7 , wherein L is selected from the group consisting of —OCH 2 — and —NHCH 2 —.
9 . The compound of claim 7 , wherein L is selected from the group consisting of —CH═CH— and —C≡C—.
10 . The compound of claim 7 , wherein L is selected from the group consisting of —SCH 2 —, —SO 2 —, and —CH 2 SO—.
11 . The compound of claim 1 , wherein L comprises a —W—C(═V)— group, where V and W are each individually selected from O, S or NH.
12 . The compound of claim 11 , wherein:
L comprises a —OC(═O)— group or —NHC(═O)— group;
P 2 is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and
Z consists of 5 atoms selected from oxygen, nitrogen, sulfur and hydrogen.
13 . The compound of claim 12 , wherein:
L is selected from the group consisting of —OC(═O)— and —NHC(═O)—;
P 2 is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and
Z is —NHSO 2 —.
14 . The compound of claim 13 , wherein P 2 is
15 . The compound of claim 12 , wherein:
L comprises a —OC(═O)— group;
P 2 is substituted heterocyclic;
R 5 is C(O)OR 8 ; and
R 8 is C 1-6 alkyl.
16 . The compound of claim 11 , wherein:
L comprises a —OC(═O)— group or —NHC(═O)— group;
P 2 is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and
P 1 ′ is alkyl, alkenyl, or aryl.
17 . The compound of claim 11 , wherein:
L comprises a —OC(═O)— group;
P 2 is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and
P 1 ′ is methyl, propyl, butyl, cyclopropyl or phenyl.
18 . The compound of claim 17 , wherein:
L is —OC(═O)—;
P 2 is a substituted heterocyclic;
R 5 is C(O)OR 8 ; and
R 8 is C 1-6 alkyl.
19 . The compound of claim 1 , wherein L is selected from the group consisting of ester, amide, carboxy, carbamate, thioester, and thioamide.
20 . The compound of claim 1 , wherein P 2 is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81.
21 . The compound of claim 20 , wherein L consists of from 1 to 5 atoms selected from the group consisting of carbon and oxygen.
22 . The compound of claim 20 , wherein P 2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle.
23 . The compound of claim 1 of the formula
24 . The compound of claim 23 , wherein L is selected from the group consisting of —WC(═V)—NH— and —WC(═V)—O—, where V and W are each individually selected from O, S or NH.
25 . The compound of claim 23 , wherein the C 13 -C 14 double bond is cis.
26 . The compound of claim 23 , wherein the C 13 -C 14 double bond is trans.
27 . The compound of claim 23 , wherein P 2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle.
28 . The compound of claim 23 , wherein L consists of from 1 to 5 atoms selected from the group consisting of carbon and oxygen.
29 . The compound of claim 23 , wherein L consists of from 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur.
30 . The compound of claim 29 , wherein L is selected from the group consisting of —OCH 2 — and —NHCH 2 —.
31 . The compound of claim 29 , wherein L is selected from the group consisting of —CH═CH— and —C≡C—.
32 . The compound of claim 29 , wherein L is selected from the group consisting of —SCH 2 —, —SO 2 —, and —CH 2 SO—.
33 . The compound of claim 23 , wherein L comprises a —W—C(═V)— group, where
V and W are each individually selected from O, S, or NH.
34 . The compound of claim 33 , wherein:
L comprises a —OC(═O)— group or —NHC(═O)— group;
P 2 is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and
Z consists of 5 atoms selected from the group consisting of oxygen, nitrogen, sulfur and hydrogen.
35 . The compound of claim 34 , wherein:
L is selected from the group consisting of —OC(═O)— and —NHC(═O)—;
P 2 is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and
Z is —NHSO 2 —.
36 . The compound of claim 34 , wherein:
L comprises a —OC(═O)— group;
P 2 is a substituted heterocyclic;
R 5 is C(O)OR 8 ; and
R 8 is C 1-6 alkyl.
37 . The compound of claim 33 , wherein:
L comprises a —OC(═O)— group or —NHC(═O)— group;
P 2 is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and
P 1 ′ is alkyl, alkenyl, or aryl.
38 . The compound of claim 37 , wherein:
L comprises a —OC(═O)— group;
P 2 is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and
P 1 ′ is methyl, propyl, butyl, cyclopropyl or phenyl.
39 . The compound of claim 38 , wherein:
L is —OC(═O)—;
P 2 is a substituted heterocyclic;
R 5 is C(O)OR 8 ; and
R 8 is C 1-6 alkyl.
40 . The compound of claim 38 , wherein P 2 is
41 . The compound of claim 23 , wherein L is selected from the group consisting of ester, amide, carboxy, carbamate, thioester, and thioamide.
42 . The compound of claim 23 , wherein P 2 is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81.
43 . The compound of claim 42 , wherein L consists of from 1 to 5 atoms selected from the group consisting of carbon and oxygen.
44 . The compound of claim 42 , wherein P 2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle.
45 . The compound of claim 1 of the formula
46 . The compound of claim 45 , wherein L is selected from the group consisting of —WC(═V)—NH— and —WC(═V)—O—, where V and W are each individually selected from O, S or NH.
47 . The compound of claim 45 , wherein the C 13 -C 14 double bond is cis.
48 . The compound of claim 45 , wherein the C 13 -C 14 double bond is trans.
49 . The compound of claim 45 , wherein P 2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle.
50 . The compound of claim 49 , wherein P 2 is
51 . The compound of claim 45 , wherein L consists of from 1 to 5 atoms selected from the group consisting of carbon and oxygen.
52 . The compound of claim 45 , wherein L consists of from 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur.
53 . The compound of claim 52 , wherein L is selected from the group consisting of —OCH 2 — and —NHCH 2 —.
54 . The compound of claim 52 , wherein L is selected from the group consisting of —CH═CH— and —C≡C—.
55 . The compound of claim 52 , wherein L is selected from the group consisting of —SCH 2 —, —SO 2 —, and —CH 2 SO—.
56 . The compound of claim 45 , wherein L comprises a —W—C(═V)— group, where V and W are each individually selected from O, S, or NH.
57 . The compound of claim 56 , wherein:
L comprises a —OC(═O)— group or —NHC(═O)— group;
P 2 is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and
Z consists of 5 atoms selected from the group consisting of oxygen, nitrogen, sulfur and hydrogen.
58 . The compound of claim 57 , wherein:
L is selected from the group consisting of —OC(═O)— and —NHC(═O)—;
P 2 is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and
Z is —NHSO 2 —.
59 . The compound of claim 57 , wherein:
L comprises a —OC(═O)— group;
P 2 is a substituted heterocyclic;
R 5 is C(O)OR 8 ; and
R 8 is C 1-6 alkyl.
60 . The compound of claim 56 , wherein:
L comprises a —OC(═O)— group or —NHC(═O)— group;
P 2 is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and
P 1 ′ is alkyl, alkenyl, or aryl.
61 . The compound of claim 60 , wherein;
L comprises a —OC(═O)— group;
P 2 is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and
P 1 ′ is methyl, propyl, butyl, cyclopropyl or phenyl.
62 . The compound of claim 61 , wherein:
L is —OC(═O)—;
P 2 is a substituted heterocyclic;
R 5 is C(O)OR 8 ; and
R 8 is C 1-6 alkyl.
63 . The compound of claim 45 , wherein L is selected from the group consisting of ester, amide, carboxy, carbamate, thioester, and thioamide.
64 . The compound of claim 45 , wherein P 2 is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81.
65 . The compound of claim 64 , wherein L is a linker group consisting of from 1 to 5 atoms selected from the group consisting of carbon and oxygen.
66 . The compound of claim 64 , wherein P 2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle.